HeV F protein schematic and fusion model. (A) Diagram of the fusion-active, disulfide (S-S)-linked F protein with the HeV F TMD sequence below. Domain structure includes the fusion peptide (FP), heptad repeat A (HRA), HRB, TMD, and the cytoplasmic tail (CT). In the fusion model, the TMDs of the metastable prefusion F interact as a trimer (B). Then triggering of F leads to dissociation of the TMDs and the HRB domains (C). Changes in TMD interactions promote extension of the HRA domains and insertion of the FP into the target membrane (D). (E and F) Further refolding of F leads to formation of the postfusion six-helix bundle conformation.